📄 Archived: 2025-08-12 12:45:56 UTC
🔗 Source: https://old.reddit.com/r/estrogel/comments/1bpj9o2/hacking_yaptaz_mechanosensor_against_skin_aging/

# Hacking YAP/TAZ mechanosensor against skin aging (in the future)

r/estrogel • by u/darthemofan • 7 points

# Paper and links

This is a review of "YAP/TAZ activity in stromal cells prevents ageing by controlling cGAS-STING" in Nature. 2022 Jul 1; 607(7920): 790–798.

medline: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7613988/

pdf: on https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7613988/pdf/EMS158105.pdf

# YAP/TAZ our old friend for scarless healing

I love to talk about verteporfin and its potential for scarless healing: understanding how verteporfin scarless healing works under the hood was very instructive.

YAP/TAZ is a mechanosensor for the cells: it detects tearing and shearing.

In mammals, this detection causes the activation of a pathway that creates a scar - but we still have "under the hood" in our cells the same ability for scarless regeneration as seen in other species, so if you put something that blocks YAP/TAZ mechanosensor (such as verteporfin), then there's no scar, and the tissues heals perfectly - with hair follicule and everything!

Personally, I can't wait to buy some verteporfin to test on myself! (2 small problems: I don't have any surgery planned that should leave a large scar, and there's a worldwide shortage, but a good friend told me it's available in China, so I'll see what I can do)

But this begs the questions: wtf is YAP/TAZ doing when you don't have a gaping wound?

In the human body, most things are multipurpose, so it should play some other kind of role the rest of the time. This is the principle of "no free lunch": blindly putting verteporfin anywhere like some kind of holy water should be bad - and if we don't know just "how bad", it means we don't know nothing.

# TLDR: YAP/TAZ other job: limit aging

We now about the scar stuff, but YAP/TAZ is mostly involved in preventing senescence, by sensing the force applied to the cell (it's a mechanosensor) and respond to them by maintaining the ECM (extra cellular matrix)

Think about cells as being surrounded by a bunch of stuff: the stuff is the ECM (made of collagen elastin etc). When cells detect mechanical forces, the feedback loop is they make a little more ECM, to limit the tearing/shearing.

Compared to scarless healing, that means YAP/TAZ works the other way around: a knockout (removing the normal function) should give you a animal with scarless healing (unfortunately, something they didnt check) yet it would come at a price: faster ageing!

Here I'm jumping a big ahead, but let's look at how the paper came to these conclusions

# YAP/TAZ knockout gives a faster aging mouse

> "To experimentally mimic the decline of YAP/TAZ activity during physiological ageing, we carried out YAP/TAZ inactivation in stromal cells of young adult mice (...) YAP/TAZ were genetically deleted by Tamoxifen administration at 2.5 months of age, and mice were analyzed after 5-8 weeks (see Methods). Histopathological assessment of the skin of young Col-YAP/TAZ cKO mice showed a decreased number of fibroblasts (Fig. 2a, b and Extended Data Fig. 2b), upregulation of Cdkn1a mRNA (Fig. 2c and Extended Data Fig. 2c), and aberrant collagen deposition (Extended Data Fig. 2d, e), all established phenotypes of the ageing dermis11,14. YAP/TAZ ablation in dermal fibroblasts also led to non-cell-autonomous effects, such as reduction of subcutaneous fat and reduced density of hair follicles (Fig. 2d), well-known traits of the ageing skin15. In addition, the phenotype of Col-YAP/TAZ cKO mice overlaps with that of old mice"

After being captivated by the introduction and this detail (and it's just the beginning of the paper!), I thought, we're not so interested in artificially aging mices, but keeping them young and healthy.

# Inducing YAP/TAZ prevent this

Well, doing "pulses" of YAP/TAZ activity with doxycyclin-inducible transgenes helps keep these faster aging mice in good health:

> "In light of the above results on YAP/TAZ cKO mice, and given that declining YAP/TAZ activity accompanies physiological ageing, we next asked whether the converse experiment - experimentally sustaining YAP/TAZ activity - could delay or suppress features of ageing. For this, we used mice carrying a doxycycline-inducible transgene encoding active YAP (TetO-YAPS127A;R26-rtTAM2)16; starting from 3 months of age, mice were kept under a pulsating regimen of YAP expression (as measured by western blot on tail tip fibroblasts, Extended Data Fig. 2g) by administering low doses of doxycycline twice a week until they reached more than 21 months of age. We found that sustaining YAP function prevented several features of ageing, rescuing fibroblast density (..) and hair follicle density (Fig. 2d), all to levels comparable to those of younger mice."

So not only the mice didn't loose their hairs, but they also had good arteries:

> "We next extended these conclusions to a second example of declining YAP/TAZ mechanosignalling during ageing, that is the aortic wall" (..) Thus, YAP/TAZ mechanotransduction in aortic SMCs is an essential signal integral to the youthful homeostasis of the aortic wall, and its attenuation drives pathological features typically associated with natural ageing.

# YAP/TAZ mechanosensor needs a working ECM

After reading that, my first thought was: "could YAP/TAZ involvement in skin aging simply be a reduced signal sensibility due to the ECM degradation?

They indirectly tested the ECM idea by looking at mutations of Fibrillin-1: it does to the aorta the same changes as seem in aging, but again pulsing YAP/TAZ stopped progression of aorta elastic aging:

> "If YAP/TAZ mechanotransduction is relevant for controlling the ageing process, then attenuating mechanotransduction through direct manipulation of the ECM should also favor the emerge of ageing phenotypes, and in a manner driven by YAP/TAZ inhibition. An ideal playground to test this hypothesis is represented by mutations in Fbn1, which encodes Fibrillin-1 - an adhesive protein associated with the elastic fibers." (..) As visualized by immunofluorescence for YAP/TAZ, p-MLC2 and by western blot for p-FAK, we found that Fbn1 mutation recapitulates, in a few months, the mechanosensing decline that normally occurs over a lifetime (Fig. 3c, d and Extended Data Fig. 3d-f).

They didn't directly test the ECM idea, but it's a good enough proxy!

# YAP/TAZ shows all the signs of actual aging

It's the real aging stuff: take old cells and put them in a culture: they're still old

> "old fibroblasts, analyzed shortly after explantation, retain the same cytoplasmic YAP/TAZ bias they display in vivo"

The cells also shows a SASP (senescence associated secretion profile) and beta-galactosidase, 2 well known hallmarks of aging, so it's likely YAP/TAZ causes both scarred healing (upon injury) and anti aging functions (upon normal condition):

> "Loss of YAP/TAZ in cultured fibroblasts also activates senescence-associated β-Galactosidase (SA-β-Gal), a classic marker of senescence (Extended Data Fig. 4f), consistent with prior in vitro findings. (..) experimentally sustaining YAP/TAZ activity rejuvenated these cells, suppressing SASP and SA-β-Gal expression (Fig. 4b, Extended Data Fig. 4g,h). SASP suppression was also attained by sustaining endogenous mechanotransduction and YAP/TAZ nuclear levels, through treatment with the integrin agonist pyrintegrin22"

And it goes both ways:

> "Conversely, senescence was readily induced in young fibroblasts by experimental attenuation of YAP/TAZ mechanotransduction through inhibition of Rho-GTPases (Extended Data Fig 4k, l), one of the key upstream inputs that, by modulating the actin cytoskeleton, positively controls YAP/TAZ activity6. Thus, induction of senescence in old fibroblasts functionally associates to declining YAP/TAZ function."

# Finding ways to hack YAP/TAZ

YAP/TAZ mechanosensing is needed to limit senescence and if it's prevented for working by making a super rigid ECM, things like those seen in aging happen:

> "Next, we investigated the role of mechanical cues in the regulation of the YAP/TAZ-cGAS axis. For this, we inhibited YAP/TAZ activity by plating fibroblasts on compliant ECM-hydrogels, as such reducing the pulling forces from the ECM6. Mechanical inhibition of YAP/TAZ led to activation of cGAS, which was indeed rescued by adding back YAP (Extended Data Fig. 6a,b). Similarly, in another model of low tensional state (cellular confinement onto small adhesive areas6), mechanical inhibition of endogenous YAP/TAZ also triggered activation of cGAS (Extended Data Fig. 6c); under these conditions, cells are forced to adopt a more rounded morphology, a phenomenon that has also been observed in human dermal fibroblast during ageing"

The most interesting is how it works under the hood, and how it can be avoided even if the ECM "rigidity" couldn't be fixed, by using drugs: then all the bad things can be avoided by inactivating STING!

> "in the skin of YAP/TAZ cKO; STINGGt/Gt mice, STING inactivation prevented loss of fibroblasts and preserved youthful ECM organization, subcutaneous fat layer and hair follicle density" (..) Taken together, these data indicate that YAP/TAZ restrain cGAS-STING signalling during adult tissue homeostasis in vivo, preventing emergence of senescent cells, of a proinflammatory microenvironment and age-related tissue dysfunction"

That's a super long and detailed paper, each of the experiment would by themselves be worthy of a standalone paper. The coherent whole is worthy of nature!

# Putting it all together

Let's look at the discussion:

> "Here we identified a molecular mechanism regulating in vivo cell senescence and ageing centered on the YAP/TAZ-cGAS-STING signalling conduit (..) we show that physiological ageing of multiple tissues parallels declining mechanotransduction, as visualized by attenuated YAP/TAZ activity and reduced cellular mechanosignalling. Future work will be required to further dissect the intimate causes underlying changes in mechanotransduction during ageing; these may be due, for example, to alterations in the physical properties of the ECM, in the viscoelastic properties of the whole tissue, in integrin-ECM association, or linked to more cell intrinsic alterations, such as defective contractility, or other changes."

So they aren't fully certain the ECM degradation,

> "The findings break new ground on the nature of the signals and mechanisms inducing senescence in vivo. Depletion of senescent cells by senolytics has been shown to ameliorate ageing traits as such connecting accumulation of senescent cells to ageing1,2. Yet, the upstream molecular events that induce senescence in living tissues have so far remained unclear"

But now we know at least 1 cause of senescence!

> "The identity of the cell types initiating senescence in living tissues remains poorly investigated. Here we found that waning levels of YAP/TAZ mechanotransduction is not a generalized feature of all cell types but occurs primarily in stromal and contractile cells. It is in these same cell types that we validated the YAP/TAZ-cGAS-STING connection to senescence and ageing-related tissue dysfunctions; it is thus tempting to propose that ageing may primarily initiate in tissues providing the structural framework and mechanical support to mammalian organs"

And it's at least as important as scarless healing:

> "Irrespectively, the endogenous function of YAP/TAZ as regulator of senescence in adult tissues in vivo, and in specific cell types, remained unexplored, let alone the role of YAP/TAZ in ageing. The present results establish YAP/TAZ as factors playing physiological functions in youthful tissue homeostasis. This represents a departure from the current view of YAP/TAZ as relevant for cancer and tissue regeneration but irrelevant for normal adult homeostasis, as inferred by the inconsequentiality of YAP/TAZ genetic ablation in many epithelial tissues49"

And it can be used to limit aging, at least in vitro

> "Our work contributes to fill this gap by showing that STING inhibition in vivo is sufficient to prevent accrual of senescent cells and, in so doing, the later emergence of accelerated ageing traits"

And why:

> "YAP/TAZ activity is in turn instrumental to preserve the mechanical resilience of the nuclear envelope. This raises the possibility of mechanically regulated feedback loops between YAP/TAZ and the physical attributes of the nucleus and the cytoskeleton to be explored in future work, and particularly in the context of ageing biology."

And how:

> "STING inhibition may represent a valid alternative to current senolytics approaches, aiming to preserve tissue integrity by preventing senescence rather than eliminating cells"

# My conclusions

It's an absolutely incredible groundbreaking work that'll certainly lead to major advances in healthcare ... and skincare!

If you activate YAP/TAZ mechanosensor or inhibit STING, it should stop the tissue aging, as is shown in their aorta examples, and maybe even rejuvenate them if the process is enough to restores the ECM (so make elastin, collagen etc), as the cells could then "sense" again the forces, and maintain their ECM.

Eventually, it should make it possible to "undo" the UV damage (80% of facial skin aging), so that the facial skin is like sun-protected skin (which responds well to E2 or E3!)

The only thing we need is something that:

- either does the opposite of verteporfin and instead of "disabling" the mechanosensor (like, disconnecting the sensors: an antagonist) pushes the trigger (an agonist)
- or disables STING (like they did in the paper)

Given what we keep learning about YAP/TAZ, I have no doubt that we'll get eventually drugs like that in a few years.

In the meantime, scarless healing is already a very cool thing, and verteporfin is an FDA approved drug. The shortages suck though!

# Suggested side readings

As a more accessible version of the paper, another paper that's more a comment on this original work https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9632523/

For the ECM aging, elastin is what matters first: it declines after 25, while collagen declines after 60.

While it's mostly focused on what's regulating elastin transcription, this paper has a good intro: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9448287/

Many papers attempt to increase elastin by making peptides, to talk about things like matrixmetalloproteases (MMP) check https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10408523/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9827338/ : just focus on the introduction and the discussion.

For a recent paper on the E2 effect on the ECM, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10813671/

## Comments

u/MH040404 • 3 points

Verteporfin has been used by some hair transplant surgeons with some descent success. Dr Quazi in California is trying to do a small trial on facial scars ( I think he is still looking for candidates) . If it’s a doctor or research facility ordering it, it’s available on some chemist sites like medichem express etc.

u/darthemofan • 3 points

BTW I creeped up your profile and found these links that other ppl here might find helpful:

https://www.realself.com/review/microneedling-incision-burn-scar-legs-forehead-verteporfin

microneedle + injection, % unknown but explains the process use a sonicator, so it's likely a simple dilution from the powder

https://www.realself.com/review/scarless-after-verteporfin-injected-scar-revision

injected 0.1ml of 2mg/ml concentration per cm

https://www.reddit.com/r/AcneScars/comments/18pfxvw/verteporfin

scar removal + injection on the surgery day

btw mh040404 you know a whole lot ab verteporfin.

do you have a scar bothering you? is there any way I can help you? like, do you want a recipe to make your own from raws?

you can let any cosmetic surgeon do your scal removal: just inject yourself right after surgery. syringes are easy to get, and injection isn't rocket science

u/[deleted] • 2 points

Wow this is really interesting. I'm glad I'm subbed to this place, there's really informative posts on here I wouldn't have found otherwise.

I'm hopefully getting surgery in a while, so the potential of verteporfin would be useful. Of course I'll have to read more about it myself, but still, I didn't know that was a thing before now.

u/darthemofan • 3 points

> I didn't know that was a thing before now

not yet, but we'll make it into one

here we innovate around problems - there was no DIY transdermal from raws 4 years ago. now there is, bc we did the work